Stem cells include both embryonic and adult stem cells. Adult stems cells include, but are not limited to, hematopoietic stem cells, endothelial stem cells, neural stem cells, muscle stem cells and epithelial stem cells. See Tepper, et al., Plastic and Reconstructive Surgery, 111:846-854 (2003). During embryonic and post-natal development, these stem/progenitor cells are located in their respective target organs, where they directly contribute to organogenesis, hematopoiesis, angiogenesis, neurogenesis, etc. In the adult, organs have been formed completely, and multipotent stem/progenitor cells are retained in mitotic quiescence, mostly in the bone marrow (BM), or in target organs (e.g., brain, skeletal and heart muscle, etc.).
In response to physiological stress or injury (e.g., myeloablation, ischemia, etc.), multipotent stem/progenitor cells are mobilized from their quiescent niche under the guidance of chemo- and cytokines, such as SDF1α, G-CSF, VEGF and PlGF.(1-3) Subsequently, they migrate specifically to the damaged organ sites (e.g., hematopoietic, endothelial and epithelial stem cells migrate systemically via blood vessels to sites of tissue ischemia or lung injury; hematopoietic, neural and muscle stem cells migrate locally in the BM, brain and muscle), where they home, integrate and contribute to tissue salvage and regeneration. See Kaushal, et al., Nat. Med., 7:1035-1040 (2001). Conversely, malignant tumor formation, growth and dissemination are caused by expansion and mobilization of so-called cancer stem cells, or supported by mobilized BM-derived (stem/progenitor) cells.
Therefore, a detailed understanding of the molecular mechanisms of retention, proliferation, and recruitment of stem/progenitor cells can result in targeted expansion of the therapeutic armament, both for increased tissue salvage and regeneration, as well as for prevention of cancer growth and dissemination. Hematopoietic and endothelial stem/progenitor cells are retained in the bone marrow (BM) niche via receptor-ligand interactions and mobilized from the BM after proteolytic degradation of these retention complexes, yet the proteinases and retention signals involved remain incompletely identified. It is, however, known that proteases are involved in stem cell mobilization, i.e., up-regulated activity of MMP-9 and neutrophil elastase. These proteases mediate cleavage of anchor molecules (e.g., membrane-bound Kit ligand), thereby liberating quiescent stem/progenitor cells and making them permissive for proliferation and migration. Moreover, BM-derived proteases modulate chemo- and cytokine levels and remodeling of the BM extracellular matrix, resulting in proliferation and migration to the peripheral circulation.(13-14) Conversely, BM-derived proteases also mediate the development and dissemination of malignancy, as neutrophil elastase, taspase and MMPs are implicated in the pathogenesis of leukemia and multiple myeloma. In addition, the identification of the important retention signals involved in keeping the stem/progenitor cells in their quiescent niche, remains incomplete. Several molecules, such as CD26, integrins, CD44, E-selectin, VCAM, etc., have already been identified. However, the identification of novel retention signals is not only important for the development of novel mobilization strategies, but may also improve stem cell isolation, homing and engraftment. The role of the plasmin proteinase system for the mobilization of stem/progenitor cells that reside in the bone marrow remains elusive. However, members of the plasminogen family (e.g., uPA, tPA, uPA receptor (uPAR), plasminogen receptor (Annexin II)) were found to be expressed in the BM, and were associated with leukemia and multiple myeloma.(15-16) 